Health Disparities, Inequities, and Social Determinants of Health in Multiple Sclerosis and Related Disorders in the US: A Review.

Importance: There is empirical evidence that social determinants of health (SDOH) impact health outcomes in Black and Hispanic and Latinx individuals in the US. Recently, SDOH have risen to the top as essential intervention targets that could help alleviate racial and ethnic disparities. Neuromyelitis optica spectrum disorder (NMOSD) disproportionately affects Black individuals, and multiple sclerosis (MS) has seen a recent shift in select racial groups. It is unclear to what degree SDOH have been investigated and contribute to racial and ethnic health disparities and inequities. Observations: This narrative review provides a contemporary synthesis of SDOH associated with racial and ethnic health disparities and inequities in MS, NMOSD, and other autoimmune disorders, such as myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated disease. These immune-mediated neurological diseases were chosen for their capacity to be a high burden to society and because of complementary SDOH-associated challenges among minority populations. A paucity of research addressing inequities and the role of SDOH in MS and NMOSD was noted despite findings that Black individuals have a higher risk of developing MS or NMOSD and associated mortality compared with White individuals. Greater health disparities were also found for those with lower income and education, lower health literacy, and negative illness perceptions in MS. No studies in MOG-Ab disorders were found. Conclusions and Relevance: Increased efforts are needed to better understand the role of SDOH in racial and ethnic health disparities and inequities in MS, NMOSD, and emerging autoimmune disorders. This includes developing research frameworks aimed at understanding the magnitude and interrelationships of SDOH to better develop system-based multilevel interventions across the spectrum of care for these neurological conditions.

Is Asian type MS an MS phenotype, an NMO spectrum disorder, or a MOG-IgG related disease?

BACKGROUND: A specific particularity of neurological diseases in Asia is the relative commonality of neuromyelitis optica (NMO) and Asian type MS (OSMS). Both conditions also occur in South American patients. The Brazilian population differs from the European and the Asian populations due to the mixture of ancestralities between European colonizers and African slaves. To better know the clinical characteristics of Brazilian patients with Asian type MS this study aimed to analyze the clinical, radiological and serological data that would help to distinguish between OSMS and NMO and clarify, in a Non-Asian population, if OSMS is an MS phenotype, an NMO spectrum disorder by 2015 classification, or a complement activating antibody to myelin oligodendrocyte glycoprotein (MOG-IgG) antibody-related disease. METHODS: We selected cases retrospectively with NMO and OSMS in the medical registry of patients with idiopathic inflammatory demyelinating diseases under follow-up since 1997 in Federal Hospital da Lagoa, the principal reference center for MS treatment in Rio de Janeiro, Brazil. OSMS has selective involvement of the optic nerve and spinal cord with no cerebral or cerebellar symptoms associated with small spinal cord lesions and negativity for the aquaporin-4 antibody (AQP4-IgG). NMO full-filled the revised criteria (2006) associated with longitudinally extensive transverse myelitis (LETM). We recorded the following data: ethnicity/skin color, neurologic impairment "at nadir" and "at recovery" of the index events (optic neuritis and transverse myelitis), long term disability, mortality, health quality of life scores by the SF-36 questionnaire, CSF IgG oligoclonal bands and serological AQP4-IgG and MOG-IgG antibodies tested by Cell-based assay. The last brain MRIs were classified as either satisfying or not satisfying MAGNIMS radiologic criteria for MS or typical or not typical for NMOSD. The new classification of NMO spectrum disorders (2015) was applied. RESULTS: Forty-one OSMS and 122 NMO cases were analyzed. OSMS affected mainly young white women, causing unilateral optic neuritis and partial myelitis with excellent recovery. After a mean disease duration of 20 years, 90% of the patients had free ambulation, and 70% had a mild disability or no disability. Only 7.2% presented a secondary progressive course, and no deaths occurred. All cases had negativity to AQP4-IgG and MOG-IgG biomarkers. 95% had resonance criteria for MS. OSMS differed from NMO by ethnicity, morbidity, and mortality: most were African descendants, with severe motor and visual dysfunction, and one third died. Only NMO cases full-filled the new NMOSD classification (52 AQP4-IgG positive, 29 AQP4-IgG negative, and 41 AQP4-IgG unknown). CONCLUSION: In Brazilian patients, OSMS and NMO are different immune-mediated diseases. OSMS is a milder MS phenotype.

Evaluation of ethnicity as a predictor of diagnostic phenotype and prognosis in neuromyelitis optica spectrum disorder in Toronto, Canada.

BACKGROUND: Recent international studies suggest that ethnicity may predict relapse types and outcomes in NMOSD. Our aim was to evaluate ethnicity as a predictor of diagnostic phenotype and prognosis in a multi-ethnic NMOSD cohort from a single geographic region. METHODS: This was a multi-centre retrospective cohort study of NMOSD subjects in Toronto, Canada. Ethnicity was classified as Asian, black, Caucasian, and other. Regression models were used to assess the relationship between ethnicity and each of diagnostic phenotype (2006 vs. only 2015 diagnostic criteria), annualized relapse rate, and EDSS at last follow-up. RESULTS: Out of 81 patients with NMOSD, 87.7% were female, 70.4% positive for aquaporin-4 (AQP4) IgG, with mean age of onset 38.9 (17) years and median disease duration [IQR] of 9.8 [4.50, 16.59] years. Blacks compared to Asians were less likely to exhibit classic NMO as per 2006 diagnostic criteria (p = 0.006). Caucasians, compared to Asians, had lower EDSS scores at last follow-up (p = 0.008) despite a trend towards higher annualized relapse rates. Older age of onset was significantly associated with greater disability as measured by the EDSS (p = 0.003). CONCLUSIONS: In this multi-ethnic cohort from Toronto, Canada, blacks with NMOSD were less likely than Asians to demonstrate classic NMO by 2006 diagnostic criteria. Caucasians had better long-term disability outcomes compared to Asians as measured by the EDSS.

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD.

Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD.

Outcome prediction models in AQP4-IgG positive neuromyelitis optica spectrum disorders.

Pathogenic antibodies targeting the aquaporin-4 water channel on astrocytes are associated with relapsing inflammatory neuromyelitis optica spectrum disorders. The clinical phenotype is characterized by recurrent episodes of optic neuritis, longitudinally extensive transverse myelitis, area postrema attacks and less common brainstem and cerebral events. Patients often develop major residual disability from these attacks, so early diagnosis and initiation of attackpreventing medications is important. Accurate prediction of relapse would assist physicians in counselling patients, planning treatment and designing clinical trials. We used a large multicentre dataset of 441 patients from the UK, USA, Japan and Martinique who collectively experienced 1976 attacks, and applied sophisticated mathematical modelling to predict likelihood of relapse and disability at different time points. We found that Japanese patients had a lower risk of subsequent attacks except for brainstem and cerebral events, with an overall relative relapse risk of 0.681 (P = 0.001) compared to Caucasians and African patients, who had a higher likelihood of cerebral attacks, with a relative relapse risk of 3.309 (P = 0.009) compared to Caucasians. Female patients had a higher chance of relapse than male patients (P = 0.009), and patients with younger age of onset were more likely to have optic neuritis relapses (P < 0.001). Immunosuppressant drugs reduced and multiple sclerosis disease-modifying agents increased the likelihood of relapse (P < 0.001). Patients with optic neuritis at onset were more likely to develop blindness (P < 0.001), and those with older age of onset were more likely to develop ambulatory disability. Only 25% of long-term disability was related to initial onset attack, indicating the importance of early attack prevention. With respect to selection of patients for clinical trial design, there would be no gain in power by selecting recent onset patients and only a small gain by selecting patients with recent high disease activity. We provide risk estimates of relapse and disability for patients diagnosed and treated with immunosuppressive treatments over the subsequent 2, 3, 5 and 10 years according to type of attack at onset or the first 2-year course, ethnicity, sex and onset age. This study supports significant effects of onset age, onset phenotype and ethnicity on neuromyelitis optica spectrum disorders outcomes. Our results suggest that powering clinical treatment trials based upon relapse activity in the preceding 2 years may offer little benefit in the way of attack risk yet severely hamper clinical trial success.

Simulating the Impact of Elevated Levels of Interleukin-6 on the Pharmacokinetics of Various CYP450 Substrates in Patients with Neuromyelitis Optica or Neuromyelitis Optica Spectrum Disorders in Different Ethnic Populations.

A physiologically based pharmacokinetic (PBPK) model was used to simulate the impact of elevated levels of interleukin (IL)-6 on the exposure of several orally administered cytochrome P450 (CYP) probe substrates (caffeine, S-warfarin, omeprazole, dextromethorphan, midazolam, and simvastatin). The changes in exposure of these substrates in subjects with rheumatoid arthritis (and hence elevated IL-6 levels) compared with healthy subjects were predicted with a reasonable degree of accuracy. The PBPK model was then used to simulate the change in oral exposure of the probe substrates in North European Caucasian, Chinese, and Japanese population of patients with neuromyelitis optica (NMO) or NMO spectrum disorder with elevated plasma IL-6 levels (up to 100 pg/mL). Moderate interactions [mean AUC fold change, ≤ 2.08 (midazolam) or 2.36 (simvastatin)] was predicted for CYP3A4 probe substrates and weak interactions (mean AUC fold change, ≤ 1.29-1.97) were predicted for CYP2C19, CYP2C9, and CYP2D6 substrates. No notable interaction was predicted with CYP1A2. Although ethnic differences led to differences in simulated exposure for some of the probe substrates, there were no marked differences in the predicted magnitude of the change in exposure following IL-6-mediated suppression of CYPs. Decreased levels of serum albumin (as reported in NMO patients) had little impact on the magnitude of the simulated IL-6-mediated drug interactions. This PBPK modeling approach allowed us to leverage knowledge from different disease and ethnic populations to make predictions of cytokine-related DDIs in a rare disease population where actual clinical studies would otherwise be difficult to conduct.

Clinical course of neuromyelitis optica spectrum disorder in a moroccan cohort.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) was suggested to be more frequent and have specific features among populations from Africa or North Africa. However, we could not find any large study about NMOSD in an African population in the medical literature. OBJECTIVES: To describe the characteristics of NMOSD in a Moroccan monocenter population. PATIENTS AND METHODS: A retrospective study was conducted. Patients fromJanuary 1999 to December 2015 fulfilling the 2015 International Consensus Criteria for NMOSD were included. RESULTS: Sixty four patients fulfilled the criteria. Mean age at onset was 35.7 ±â€¯10.7 years, and the sex ratio was 1/3.57. First clinical event was represented by optic neuritis (38.1%), followed by myelitis (27.0%) and a Devic's syndrome (17.2%). Mean annualized relapse rate was 1.07 ± 1.23 and mean EDSS at last visit was 5.1 ±â€¯2.8. Aquaporine 4 antibodies were positive in 47.1%. Brain lesions were found in 71.2%. Most patients (76.6%) received disease-modifying therapy, mainly cyclophosphamide (86.0%) and 49% remained relapse-free after treatment initiation CONCLUSION: Data from our study suggest more similarities between North African NMOSD patients and non-Caucasian populations. More studies are needed to assess other pathological patterns and compare disease course to other populations.

A nationwide epidemiological study on the prevalence of multiple sclerosis and neuromyelitis optica spectrum disorder with important multi-ethnic differences in Malaysia.

OBJECTIVES: This study looked at observed crude prevalence/incidence of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) in Malaysia and identified any inter-ethnic differences for MS/NMOSD. METHODS: This was a nationwide tertiary hospital-based retrospective cross-sectional study using the capture-recapture method. It looked at the estimated crude prevalence of confirmed MS and NMOSD and annual incidence on 29 December 2017. Recapture of data was done between February and March 2018 on 1 March 2018. Public and referring private institutions were accessed. RESULTS: The survey identified 767 MS and 545 NMOSD subjects, with crude prevalence rates of 2.73 per 100,000 (95% confidence interval (CI): 2.53; 2.92 per 100,000 population) and 1.94 per 100,000 (95% CI: 1.77; 2.10 per 100,000 population) with observed crude annual incidence of 0.55 (95% CI: 0.43; 0.58) for MS and 0.39 per 100,000 (95% CI: 0.35; 0.47) for NMOSD. The MS:NMOSD ratios were 1.4:1.0. The capture-recapture method revealed 913 MS (95% CI: 910; 915.9) and 580 (95% CI: 578.8; 581.2) NMOSD with prevalence per 100,000 of 3.26 (95% CI: 3.05; 3.47) and 2.07 (95% CI: 1.90; 2.24), respectively. In the MS group, 59.4% were Malay, 16.6% Chinese, 20.5% Indian, and 3.5% were from indigenous groups. In the NMOSD group, 47.3% were Malay, 46.9% Chinese, 3.5% Indian, and 2.3% were from other indigenous groups. The ratio of NMOSD to MS among the Chinese was 2:1, but the ratio of MS to NMOSD among the Malays was 1.8:1, and that in Indians was 8.3:1. CONCLUSION: There is a modest increase in the prevalence of MS and NMOSD in Malaysia with inter-ethnic differences for MS/NMOSD.

Racial differences in neuromyelitis optica spectrum disorder.

OBJECTIVE: We aimed to evaluate racial differences in the clinical features of neuromyelitis optica spectrum disorder. METHODS: This retrospective review included 603 patients (304 Asian, 207 Caucasian, and 92 Afro-American/Afro-European), who were seropositive for anti-aquaporin-4 antibody, from 6 centers in Denmark, Germany, South Korea, United Kingdom, United States, and Thailand. RESULTS: Median disease duration at last follow-up was 8 years (range 0.3-38.4 years). Asian and Afro-American/Afro-European patients had a younger onset age than Caucasian patients (mean 36, 33, and 44 years, respectively; p < 0.001). During the disease course, Caucasian patients (23%) had a lower incidence of brain/brainstem involvement than Asian (42%) and Afro-American/Afro-European patients (38%) (p < 0.001). Severe attacks (visual acuity ≤0.1 in at least one eye or Expanded Disability Status Scale score ≥6.0 at nadir) at onset occurred more frequently in Afro-American/Afro-European (58%) than in Asian (46%) and Caucasian (38%) patients (p = 0.005). In the multivariable analysis, older age at onset, higher number of attacks before and after immunosuppressive treatment, but not race, were independent predictors of severe motor disabilities at last follow-up. CONCLUSION: A review of a large international cohort revealed that race affected the clinical phenotype, age at onset, and severity of attacks, but the overall outcome was most dependent on early and effective immunosuppressive treatment.

Multiple sclerosis and neuromyelitis optica spectrum disorders in Malaysia: A comparison in different ethnic groups.

We performed a retrospective observational analytical study looking at the frequencies and characteristics of multiple sclerosis(MS) and neuromyelitis optica spectrum disorders(NMOSD) in consecutive patients with idiopathic inflammatory demyelinating disease (IIDDs) attending three centers (2009-2017). Of 523 patients with IIDDs, there were 173 patients with NMOSD and 230 patients with MS. The percentage of NMOSD: IIDDs was 33%. The percentage of NMOSD:Total MS and NMOSD cohort was 43%. Of 141 seropositive NMOSD patients, 134(95%) were from the three main ethnic groups. The percentage of seropositive NMOSD to IIDDs and to combined MS and NMOSD was 26.9% and 35% respectively. Ratios of MS to NMOSD were nearly equal at 1.3 to 1.0, reinforcing the high ratio of NMOSD to MS in Asia. Nearly half of the Chinese cohort were seropositive ie; 71/141 (50%) with the remainder being Malays; 56/141 (39.7%) and Indians; 7/141 (5%). Amongst the other indigenous groups seropositivity was seen in 2 each of Iban, Bajau, Kadazan descent as well as one of Bidayuh origin. Comparatively, seropositivity in NMOSD is commoner amongst the Chinese compared to the Malays (p ≤ 0.005) and Indians, p ≤ 0.05 with ratios as high as 10:1. In the MS group of 230 subjects, 123(53.5%) were Malays (ratio of MS:NMOSD of 2:1), 41(17.8%) were Chinese, (ratio of MS:NMOSD of 0.5:1.0) and 54 (23.5%)were Indians (ratios of MS:NMOSD of 5:1 amongst the Indians). The remainder from East Malaysia were made up of 2 each of Kadazans, Ibans and Bajaus including 3 each of Bidayuh and Eurasian descent. Comparatively, in the NMOSD and MS cohorts a female preponderance was noted more so amongst Chinese NMOSD patients, with rare familial occurrence in both but more in Malay MS/NMOSD patients. This study also highlighted some of the inter-ethnic differences in presentation of MS and NMOSD amongst the 3 main ethnic races in Malaysia and confirms indigenous races having MS/NMOSD which needs further research. It also reviewed current literature on similar inter-ethnic differences world wide. To conclude, MS and NMOSD are the commonest demyelinating diseases seen in Malaysia with interesting inter-ethnic differences and similarities.

Cefaleia Trigêmino-autonômica e Neuromielite Óptica / Trigemino-autonomic Headache and Neuromyelitis Optica

As cefaleias trigêmino-autonômicas compartilham os aspectos clínicos da cefaleia, além de proeminentes sintomas disautonômicos crânio faciais. A Neuromielite Óptica (NMO) ou Doença de Devic é uma doença inflamatória grave, desmielinizante e auto-imune do sistema nervoso central que acomete, preferencialmente, os nervos ópticos e a medula espinhal, causando neurite óptica aguda, uni ou bilateral, e mielite transversa. O objetivo desse trabalho é relatar um caso clínico de NMO, cuja manifestação inicial é atípica. Uma revisão de literatura com as palavras-chaves Neuromielite Óptica e Cefaleia Trigêminoautonômica foi realizada no PubMed e foram selecionados os artigos e relatos de casos mais relevantes sobre o assunto. Conclui-se que estas duas doenças podem ter em comum uma alteração hipotalâmica e uma doença desmielinizante grave pode se iniciar com uma cefaleia trigêmino-autonômica. (AU)

The Trigeminal-autonomic headaches share the clinical features of headache, as well as prominent facial skull disautonomic symptoms. The Neuromyelitis Optica (NMO) or Devic's disease is a severe inflammatory disease, demyelinating and autoimmune of the central nervous system that affects mainly the optic nerves and spinal cord, causing acute optic neuritis, unilateral or bilateral, and transverse myelitis. The objective of this study is to report a case of NMO, whose initial manifestation is atypical. A literature review with keywords Neuromyelitis Optica and Trigeminal-autonomic Headache has conducted in PubMed and we have selected the most relevant articles and case reports on the subject. In conclusion, these two diseases may have a common hypothalamic disturbance and a severe demyelinating disease can start with a trigeminal-autonomic headache. (AU)

Neuromyelitis Optica (NMO IgG+) and Genetic Susceptibility, Potential Ethnic Influences.

INTRODUCTION: Neuromyelitis optica (NMO) and Multiple Sclerosis (MS) have been reported in different populations. NMO is more frequent in non-Caucasians, and clinical phenotype differences between populations are likely influenced by genetic susceptibility. In Brazil, it has been reported that NMO patients have a mainly European ancestry background. Like other autoimmune diseases, NMO has a multifactorial origin (i.e., genetics, environmental and infectious factors). Regarding the genetics of NMO, epidemiological findings suggest that a polygenic background has an important role in the development of this type of disease. In this context, various genes have been studied, such as those involved in the synthesis of the T cell beta chain receptor, the VH2-5 gene, myelin basic protein, the CTLA-4 gene, and the interleukin-1 gene. MATERIALS AND METHODS: We performed a study with the main objective of identifying candidate genes involved in the susceptibility to develop NMO in a Mexican population. RESULT: We included 35 patients with an NMO diagnosis according to the Wingerchuk 2006 criteria. The mean age of the patients was 43.3 years old (20-67), and 80 percent of the patients were women. The presence of HLA-DRB1*03 and HLA-DRB1*10 alleles were more frequent in NMO patients than in controls (n=198; p=0.03 and 0.005, respectively). CONCLUSION: There were no differences in the other alleles that have been described in MS subjects, such as HLA-DRB1*04, HLA-DRB1*08 and HLA-DRB1*13. These findings may support the hypothesis that implicated immune-genetics as a key factor in development of this type of disease.

Prevalence of neuromyelitis optica spectrum disorder in the multi-ethnic Penang Island, Malaysia, and a review of worldwide prevalence.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) occurs worldwide in all ethnicities. Recently, population-based studies have shown that NMOSD is more common among non-White populations. There is scarce data about NMOSD prevalence in South East Asian populations. METHODS: (1) A population-based study was undertaken to estimate NMOSD prevalence in the multi-ethnic Penang Island, Malaysia, comprising Chinese, Malays, and Indians. Medical records of NMOSD patients followed up at the Penang General Hospital (the neurology referral centre in Penang Island) were reviewed. The 2015 diagnostic criteria of the International Panel for NMO Diagnosis were used for case ascertainment. (2) A review of population-based prevalence studies of NMOSD worldwide was carried out. PubMed and conference proceedings were searched for such studies. RESULTS: Of the 28 NMOSD patients, 14 were residents of Penang Island on prevalence day [13 (93%) Chinese and one (7%) Malay]. All 14 patients were females and aquaporin 4 seropositive. The prevalence of NMOSD in Penang Island was 1.99/100,000 population; according to ethnicities, the prevalence in Chinese was significantly higher than in Malays (3.31/100,000 vs 0.43/100,000, respectively, p = 0.0195). CONCLUSION: Based on our and other population-based studies, among Asians, East Asian origin populations (Chinese and Japanese) appear to have higher NMOSD prevalence than other Asian ethnic groups. Worldwide, Blacks seem to have the highest NMOSD prevalence. More studies in different geographical regions and ethnic groups will be useful to further inform about potential factors in NMOSD pathogenesis.

Neuromyelitis optica spectrum disorders: long-term safety and efficacy of rituximab in Caucasian patients.

OBJECTIVE: To assess the long-term benefit-risk profile of repeated courses of rituximab in Caucasian patients affected by neuromyelitis optica (NMO) and related disorders, in everyday clinical practice. METHODS: This is a prospective observational study performed at San Raffaele Hospital, Milan, Italy. From February 2006, we recruited 21 patients affected by NMO and NMO spectrum of disorders (NMOSD) whom underwent at least one cycle of intravenous (i.v.) rituximab and then were followed for at least 2 years. RESULTS: At a mean follow-up time of 48 months, we observed a significant reduction of the annualized relapse rate (ARR), from 2.0 to 0.16 (p < 0.01); and of the median Expanded Disability Status Scale (EDSS), from 5.5 to 4.0 (p < 0.013). There were 12 patients (57%) who remained disease free during the follow-up period. Five patients (24%) reported mild hematological adverse events. Serious infectious adverse events were reported by another four patients: These were all wheelchair bound at the beginning of their rituximab treatment. CONCLUSIONS: A fixed treatment scheme of rituximab, with re-treatment every 6 months, was efficacious for NMO and NMOSD, with a good safety profile; however, to obtain an even better benefit-risk ratio, close monitoring of CD19(+) B cells should be performed before the re-treatment of patients with high-level disability, concomitant leukopenia and hypogammaglobulinemia.

Central Nervous System Idiopathic Inflammatory Demyelinating Disorders in South Americans: A Descriptive, Multicenter, Cross-Sectional Study.

The idiopathic inflammatory demyelinating disease (IIDD) spectrum has been investigated among different populations, and the results have indicated a low relative frequency of neuromyelitis optica (NMO) among multiple sclerosis (MS) cases in whites (1.2%-1.5%), increasing in Mestizos (8%) and Africans (15.4%-27.5%) living in areas of low MS prevalence. South America (SA) was colonized by Europeans from the Iberian Peninsula, and their miscegenation with natives and Africans slaves resulted in significant racial mixing. The current study analyzed the IIDD spectrum in SA after accounting for the ethnic heterogeneity of its population. A cross-sectional multicenter study was performed. Only individuals followed in 2011 with a confirmed diagnosis of IIDD using new diagnostic criteria were considered eligible. Patients' demographic, clinical and laboratory data were collected. In all, 1,917 individuals from 22 MS centers were included (73.7% female, 63.0% white, 28.0% African, 7.0% Mestizo, and 0.2% Asian). The main disease categories and their associated frequencies were MS (76.9%), NMO (11.8%), other NMO syndromes (6.5%), CIS (3.5%), ADEM (1.0%), and acute encephalopathy (0.4%). Females predominated in all main categories. The white ethnicity also predominated, except in NMO. Except in ADEM, the disease onset occurred between 20 and 39 years old, early onset in 8.2% of all cases, and late onset occurred in 8.9%. The long-term morbidity after a mean disease time of 9.28±7.7 years was characterized by mild disability in all categories except in NMO, which was scored as moderate. Disease time among those with MS was positively correlated with the expanded disability status scale (EDSS) score (r=0.374; p=<0.001). This correlation was not observed in people with NMO or those with other NMO spectrum disorders (NMOSDs). Among patients with NMO, 83.2% showed a relapsing-remitting course, and 16.8% showed a monophasic course. The NMO-IgG antibody tested using indirect immunofluorescence (IIF) with a composite substrate of mouse tissues in 200 NMOSD cases was positive in people with NMO (95/162; 58.6%), longitudinally extensive transverse myelitis (10/30; 33.3%) and bilateral or recurrent optic neuritis (8/8; 100%). No association of NMO-IgG antibody positivity was found with gender, age at onset, ethnicity, early or late onset forms, disease course, or long-term severe disability. The relative frequency of NMO among relapsing-remitting MS (RRMS) + NMO cases in SA was 14.0%. Despite the high degree of miscegenation found in SA, MS affects three quarters of all patients with IIDD, mainly white young women who share similar clinical characteristics to those in Western populations in the northern hemisphere, with the exception of ethnicity; approximately one-third of all cases occur among non-white individuals. At the last assessment, the majority of RRMS patients showed mild disability, and the risk for secondary progression was significantly superior among those of African ethnicity. NMO comprises 11.8% of all IIDD cases in SA, affecting mostly young African-Brazilian women, evolving with a recurrent course and causing moderate or severe disability in both ethnic groups. The South-North gradient with increasing NMO and non-white individuals from Argentina, Paraguay, Brazil and Venezuela confirmed previous studies showing a higher frequency of NMO among non-white populations.

Human aquaporin 4 gene polymorphisms in Chinese patients with neuromyelitis optica.

OBJECTIVE: To investigate the association between aquaporin 4 (AQP4) gene polymorphisms and Chinese patients with neuromyelitis optica (NMO). METHODS: 122 consecutive anti-AQP4 autoantibody (NMO-IgG) seropositive cases were enrolled for gene sequencing. Furthermore, ten SNPs were selected and genotyped for a case-control association analysis on 208 cases and 204 healthy subjects. RESULTS: 14 novel SNPs were identified, while there were no nonsynonymous mutations and their frequency was low. The heterozygous genotype at two 3' UTR SNPs was significantly higher in cases than controls: the A/T genotype of SNP rs1058424 (54.81% vs. 42.65%, p(adjusted)=0.024, OR=1.670, 95% CI=1.071-2.605) and the C/T genotype of SNP rs3763043 (53.85% vs. 42.65%, p(adjusted)=0.028, OR=1.638, 95% CI=1.054-2.545). Moreover, the 3' UTR haplotype ATATGGAT may be protective for NMO (7.67% vs. 12.18%, p=0.042). CONCLUSIONS: Polymorphisms in the coding region of AQP4 are unlikely to confer NMO susceptibility. However, the 3' UTR of this gene presents several polymorphic sites that may affect NMO risk in the Chinese.

Antibodies to neural and non-neural autoantigens in Japanese patients with CNS demyelinating disorders.

Anti-aquaporin 4 (AQP4) antibodies (Abs) are essential in neuromyelitis optica spectrum disorders (NMOSD), but the relationship between CNS demyelinating disorders (CNSDD) and other neural Abs remains unclear. Here we screened anti-neural Abs in the sera of 70 Japanese CNSDD patients. While two had only demyelinating events among three anti-N-methyl-d-aspartate receptor (NMDAR) Ab-positive subjects, the other subject who also had anti-AQP4 Abs experienced episodes of anti-NMDAR encephalitis and of NMOSD. Major lesions in the three anti-contactin-associated protein 2 Ab-positive subjects were infratentorial, including one co-carrying anti-AQP4 Abs. Thus, autoantibodies can be clinically silent, but multiple autoantibodies may participate in the pathogenesis.

Association between neuromyelitis optica and tuberculosis in a Chinese population.

BACKGROUND: A number of reports have described the presence of tuberculosis (TB) in neuromyelitis optica (NMO) patients. However, a definite association between the two conditions has not been conclusively demonstrated. METHODS: To investigate the association between NMO and TB in a Chinese population, we performed a retrospective review of hospital records of NMO patients, control patients and tuberculosis meningitis (TBM) patients from January 1, 1995 to December 31, 2011. RESULTS: The frequency of preceding/simultaneous active pulmonary TB (PTB) was not significantly different between NMO patients (1.1%) and control groups (2.3% in myasthenia gravis, 1.1% in polymyositis or dermatomyositis, zero in idiopathic facial palsy and viral meningitis/meningoencephalitis). NMO cases differed from TBM cases in terms of demographics, course (recurrent or monophasic), cerebrospinal fluid analysis and magnetic resonance images. Two TBM patients shared partial clinical features with NMO (one of the TBM patients had a longitudinal extensive spinal cord lesion involving the holocord, and the other had optic neuritis before anti-tuberculosis treatment). NMO antibodies were only detected in NMO patients and not in TBM patients with myelitis or optic neuritis. CONCLUSIONS: We could not confirm previous suggestions of the association between PTB and NMO. Direct infection of the central nervous system by TB may mimic NMO in some respects, but whether NMO-like symptoms that develop during the course of TB should be considered and diagnosed as NMO is open to discussion.

Brainstem manifestations in neuromyelitis optica: a multicenter study of 258 patients.

BACKGROUND: Neuromyelitis optica (NMO) is a severe autoimmune disease of the central nervous system characterized by spinal cord and optic nerve involvement. Brainstem manifestations have recently been described. OBJECTIVE: To evaluate the time of occurrence, the frequency and the characteristics of brainstem symptoms in a cohort of patients with NMO according to the ethnic background and the serologic status for anti-aquaporin-4 antibodies (AQP4-abs). METHODS: We performed a multicenter study of 258 patients with NMO according to the 2006 Wingerchuk criteria and we evaluated prospectively the frequency, the date of onset and the duration of various brainstem signs in this population. RESULTS: Brainstem signs were observed in 81 patients (31.4%). The most frequently observed signs were vomiting (33.1%), hiccups (22.3%), oculomotor dysfunction (19.8%), pruritus (12.4%), followed by hearing loss (2.5%), facial palsy (2.5%), vertigo or vestibular ataxia (1.7%), trigeminal neuralgia (2.5%) and other cranial nerve signs (3.3%). They were inaugural in 44 patients (54.3%). The prevalence was higher in the non-Caucasian population (36.6%) than in the Caucasian population (26%) (p<0.05) and was higher in AQP4-ab-seropositive patients (32.7%) than in seronegative patients (26%) (not significant). CONCLUSIONS: This study confirms the high frequency of brainstem symptoms in NMO with a majority of vomiting and hiccups. The prevalence of these manifestations was higher in the non Caucasian population.

Visual evoked potentials in neuromyelitis optica and its spectrum disorders.

Optic neuritis (ON) is a key feature of neuromyelitis optica (NMO). Recently, NMO patients of predominantly Afro-Brazilian origin were evaluated by visual evoked potentials (VEPs) and showed marked amplitude reductions. Here, we analyzed VEPs in a predominantly Caucasian cohort, consisting of 43 patients with definite NMO, 18 with anti-aquaporin (AQP) 4 antibody-seropositive NMO spectrum disorders and 61 matched healthy controls. We found reduced amplitudes in only 12.3%, prolonged latencies in 41.9% and a lack of response in 14.0% of NMO eyes. Delayed P100 latencies in eyes without prior ON suggested this was a subclinical affection. The data indicate heterogenous patterns in NMO, warranting further investigation.